Geographic Variation and Risk of Skin Cancer in US WomenDifferences Between Melanoma, Squamous Cell Carcinoma, and Basal Cell Carcinoma

Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Archives of Internal Medicine (Impact Factor: 17.33). 04/2008; 168(5):501-7. DOI: 10.1001/archinte.168.5.501
Source: PubMed
ABSTRACT
Occurrences of melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) have been associated with varying geography. Our goal was to evaluate differences in risk of these skin cancers according to residence at varying UV indices at 3 time points.
Prospective 1984-2002 study of 84 836 female nurses who lived in different UV index regions of the United States at birth and at 15 or 30 years of age. The outcome measure was diagnosis of melanoma, SCC, or BCC.
During the 18-year study, 420 cases of melanoma, 863 cases of SCC, and 8215 cases of BCC occurred. At 30 years of age, age-adjusted risks for SCC were 1.47 (95% confidence interval [CI], 1.22-1.76) and 1.90 (95% CI, 1.51-2.36) for women residing in states with a UV index of 6 (medium) and 7 or more (high), respectively. Although elevated, the age-adjusted risk of BCC at 30 years of age associated with residence in these states was substantially less. Although the risk of melanoma was not elevated for women living in these states at 30 years of age, it was significantly elevated among women living in states with UV indices of 6 at birth and at 15 years of age. There was no material change in risk estimates with multivariate adjustment. For women who reported living in states with UV indices of 7 or more at all 3 time points, the multivariate risk of SCC was highest.
The risk of SCC is independently affected by residence in locations with medium and high UV indices; the gradient of risk is weaker for BCC; and the risk of melanoma does not change significantly across this gradient.

Full-text

Available from: Graham A Colditz, Dec 07, 2014
ORIGINAL INVESTIGATION
Geographic Variation and Risk of Skin Cancer
in US Women
Differences Between Melanoma, Squamous Cell Carcinoma,
and Basal Cell Carcinoma
Abrar A. Qureshi, MD, MPH; Francine Laden, ScD; Graham A. Colditz, MD, DrPH; David J. Hunter, MBBS, DrPH
Background: Occurrences of melanoma, squamous cell
carcinoma (SCC), and basal cell carcinoma (BCC) have
been associated with varying geography. Our goal was
to evaluate differences in risk of these skin cancers ac-
cording to residence at varying UV indices at 3 time points.
Methods: Prospective 1984-2002 study of 84 836 fe-
male nurses who lived in different UV index regions of
the United States at birth and at 15 or 30 years of age.
The outcome measure was diagnosis of melanoma, SCC,
or BCC.
Results: During the 18-year study, 420 cases of mela-
noma, 863 cases of SCC, and 8215 cases of BCC oc-
curred. At 30 years of age, age-adjusted risks for SCC were
1.47 (95% confidence interval [CI], 1.22-1.76) and 1.90
(95% CI, 1.51-2.36) for women residing in states with a
UV index of 6 (medium) and 7 or more (high), respec-
tively. Although elevated, the age-adjusted risk of BCC at
30 years of age associated with residence in these states
was substantially less. Although the risk of melanoma was
not elevated for women living in these states at 30 years
of age, it was significantly elevated among women living
in states with UV indices of 6 at birth and at 15 years of
age. There was no material change in risk estimates with
multivariate adjustment. For women who reported living
in states with UV indices of 7 or more at all 3 time points,
the multivariate risk of SCC was highest.
Conclusions: The risk of SCC is independently af-
fected by residence in locations with medium and high
UV indices; the gradient of risk is weaker for BCC; and
the risk of melanoma does not change significantly across
this gradient.
Arch Intern Med. 2008;168(5):501-507
G
EOGRAPHIC LOCATION
and UV radiation have
been implicated as risk-
modifying factors for
melanoma, squamous
cell carcinoma (SCC), basal cell carci-
noma (BCC),
1-3
and breast
4
and colon
5,6
cancers. That is, UV radiation has been
shown to have a beneficial effect postu-
lated via vitamin D for some cancers, with
an increasing risk of cancer seen among
individuals residing further away from the
equator.
7-11
Ozone depletion and sea-
sonal and weather variations affect the
amount of UV radiation reaching the
earth’s surface.
12,13
The updated UV In-
dex was developed by the National
Weather Service and the Environmental
Protection Agency to predict UV radia-
tion levels on a scale from 1 to more than
11,
14,15
accounting for time of day, cloud
cover, haze, ozone concentrations, lati-
tude, and altitude.
16,17
Locations close to the equator and at
higher altitudes have higher SCC and BCC
rates.
18,19
Sustained sun exposure for long
periods results in a higher risk of SCC than
of BCC.
20-25
The incidence of BCC is higher
than that of SCC in regions with less sunny
climates and intermittent sun exposure
(BCC:SCC ratio, 3:1 to 10:1), and SCC in-
cidence increases with migration to sunny
regions, resulting in reduction of the BCC:
SCC ratio. Unlike SCC and BCC, mela-
noma does not occur preferentially on ex-
posed body sites,
26-28
and a history of
melanoma in at least 1 first-degree rela-
tive is an independent risk factor.
29
The re-
lationship between sun exposure and mela-
noma is less well established.
30
Although
a north-south gradient for melanoma risk
in the United States was seen until the
1960s, the gradient has become attenu-
ated in more recent years, with north-
south incidence rates becoming more uni-
form.
31
The latitude gradient for melanoma
Author Affiliations: Channing
Laboratory, Department of
Medicine (Drs Qureshi, Laden,
Colditz, and Hunter), and
Department of Dermatology
(Dr Qureshi), Brigham and
Women’s Hospital and Harvard
Medical School, and Program in
Molecular and Genetic
Epidemiology (Dr Hunter),
Department of Epidemiology
(Drs Laden, Colditz, and
Hunter), and Exposure,
Epidemiology, and Risk
Program, Department of
Environmental Health
(Dr Laden), Harvard School of
Public Health, Boston,
Massachusetts.
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has also been shown to be age dependent, with a slightly
higher incidence of melanoma in younger individuals liv-
ing in regions with a low UV index.
32
In Australia, a de-
crease in latitude was shown to be associated with an in-
crease in melanoma incidence in 3 states.
33
Similar trends
have been found in the United States in some studies for
light-skinned but not dark-skinned populations.
34,35
Hence, there is evidence from case-control studies both
for and against the association between geography and
melanoma risk.
The United States is the ideal model to study the effect
of geography on the risk of skin cancer because of the varia-
tion in UV indices between the northern and southern
states.
8,36,37
Estimated UV radiation exposure as a risk fac-
tor for skin cancer has been evaluated by measuring UV
levels recorded by Robertson-Berger meters placed at 30
locations across the United States.
38
A criticism of this ap-
proach has been the uncertainty of the measurements be-
cause these are estimates of real values of UV irradiation
measured at specific locations and then modeled with lati-
tude, altitude, and cloud cover. Additional criticisms of the
Robertson-Berger meter are that its spectral response curve
includes a significant amount of UV-A, which plays no role
in vitamin D production, and that the meter is tempera-
ture sensitive.
39
Individual sun exposure such as “time spent
outdoors” has been even more difficult to measure and less
reliable; this measure of sun exposure has been used in case-
control studies and is subject to substantial recall bias. At
least 1 previous study
40
has shown that UV exposure based
on residential history was associated with an increased risk
of melanoma compared with time spent outdoors, and
another study
41
showed that less sun exposure was a risk
factor for melanoma.
Data with long-term follow-up on all 3 types of skin
cancer are difficult to obtain for the same group of indi-
viduals in the United States. Data on melanoma are col-
lected via the Surveillance Epidemiology and End Re-
sults (SEER) database, but no national registries track SCC
and BCC.
42,43
From previous studies, it is not yet clear
whether melanoma risk is affected by a north-south UV
index gradient compared with SCC and BCC risks in a
population at risk of all 3 skin cancers simultaneously.
To evaluate the effect of residence at locations of vary-
ing UV indices independent of individual behavior, we
evaluated risk of melanoma, SCC, and BCC in the same
cohort of US women. We hypothesized that SCC and BCC
risks would be related to a north-south UV index gradi-
ent, and we asked whether risk of melanoma would
change significantly with this gradient.
METHODS
STUDY POPULATION
The Nurses’ Health Study (NHS) is an ongoing prospective co-
hort study that was established in 1976, when 121 700 female
registered nurses completed a mailed questionnaire that in-
cluded items about risk factors for breast cancer and other dis-
eases. At enrollment, study participants were aged 30 to 55 years
and resided in the following 11 states: California, Connecti-
cut, Florida, Maryland, Massachusetts, Michigan, New Jersey,
New York, Ohio, Pennsylvania, and Texas. These states were
originally chosen for their size and approval of the study by
the respective nursing associations. Since the cohort incep-
tion, participants now reside in every US state. The cohort is
representative of geographically diverse working women in the
United States and has a high follow-up rate. No restrictions were
made on the basis of ethnicity or race; however, the partici-
pants were 97% white, reflecting the ethnic background of
women trained as registered nurses in 1976. They have been
followed up since 1984 for skin cancer outcomes and risk fac-
tors for skin cancer, eg, natural hair color at 20 years of age,
ability to tan, and susceptibility to burn. Residential address
changes have also been recorded with every 2-year cycle. Ap-
propriate institutional human studies research approval was ob-
tained at the Brigham and Women’s Hospital.
CASE ASCERTAINMENT
Skin cancer confirmation is performed routinely. For all 3 skin
cancers, participants report new cases with each 2-year cycle.
Permission is obtained from participants to acquire medical rec-
ords if SCC or melanoma is reported; these records are re-
viewed by study physicians. Participants with SCC in situ, ac-
tinic keratoses, SCC of the oral mucosa or genitalia, melanoma
in situ, and dysplastic nevi have been excluded from this analy-
sis. Participants who self-reported SCC or melanoma before 1976
at the inception of the NHS cohort have also been excluded.
Medical records are not obtained for self-report of BCC. For
BCC, Colditz et al
44
performed a validation study in 1986 and
demonstrated that self-reports of BCC were more than 90% con-
firmed by histopathological findings. Similar high validity of
the self-reports of BCC were documented again.
45
ASSESSMENT OF GEOGRAPHIC LOCATION
Questionnaires are mailed to each participant in June of each
even-numbered year. For each cycle, follow-up is more than
90% on average, and only 4% of the nurses have been nonre-
sponders to 3 consecutive questionnaires since 1986. In 1992,
we asked about location of residence (US state) at birth and at
15 and 30 years of age.
The erythemal UV index (referred to as the UV index)isa
method to estimate UV radiation reaching the earth’s surface,
which is important for effects on human skin on a noncloudy
day. When the sun is highest in the sky, UV irradiance is
weighted by the action spectrum for erythema (redness) of white
skin. Based on the mean UV index in North America for the
month of August (by the National Oceanic and Atmospheric
Administration), the 50 states (and the District of Columbia)
were divided into the following 3 UV index groups: 5 or less
(low UV index: Alaska, Maine, Michigan, Minnesota, New
Hampshire, Oregon, Pennsylvania, Vermont, Washington, and
Wisconsin); 6 (medium UV index: Connecticut, Delaware, Il-
linois, Indiana, Iowa, Maryland, Massachusetts, Missouri, Ne-
braska, New Jersey, New York, North Dakota, Ohio, Rhode Is-
land, South Dakota, and West Virginia); and 7 or more (high
UV index: Alabama, Arizona, Arkansas, California, Colorado,
Florida, Georgia, Hawaii, Idaho, Kansas, Kentucky, Louisi-
ana, Montana, Mississippi, Nevada, New Mexico, North Caro-
lina, Oklahoma, South Carolina, Tennessee, Texas, Utah, Vir-
ginia, Washington, DC, and Wyoming). This grouping for
northern, middle, and southern states remains the same for other
months throughout the year.
STATISTICAL ANALYSIS
The cohort was restricted to women who answered all 3 ques-
tions on lifetime residence on the 1992 questionnaire and had
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not been diagnosed as having melanoma, SCC, or BCC before
1984. Participants contributed person-time from the date of re-
turn of the 1984 questionnaire. Accumulation of follow-up time
ceased at the first report of BCC, the first report followed by con-
firmation of SCC, the first report followed by confirmation of mela-
noma, death, or the return of the 2002 questionnaire, whichever
came earliest. Women with a history of other cancers were ex-
cluded. Each participant’s risk factor status was updated every 2
years on the basis of answers to the follow-up questionnaire. Cox
proportional hazards models were run for univariate analyses, and
age-adjusted rate ratios were calculated with 95% confidence in-
tervals (CIs). For multivariate models, covariates relevant to skin
cancer risk were included in the models, specifically hair color
at 20 years of age, ability to tan, and susceptibility to burn. We
chose women living in states with a low UV index (UV index,
5) as the reference group. To evaluate the skin cancer risk of
women who lived at the same location at all 3 time points, we
restricted the analysis to women who reported living in the same
state at birth and at 15 and 30 years of age.
RESULTS
COHORT CHARACTERISTICS
We found no substantial association between UV indi-
ces of the state where participants lived at birth and at
15 and 30 years of age and the ability to tan, the suscep-
tibility to burn, hair color, or the number of moles on
the left upper extremity (
Table 1). The proportion of
women with red or blonde natural hair color at 20 years
of age was slightly higher (15%) for states with a UV in-
dex of 7 or more than for those with UV indices of 5 or
less and 6 (13%). From 1984 to 2002, 420 melanoma cases
and 863 SCC cases were confirmed and 8215 BCC cases
were self-reported among 84 836 women (
Table 2), with
approximately 4 million person-years of total follow-up
time. Mean age for diagnosis of melanoma (59 years) was
less than that for SCC (62 years) or BCC (64 years). There
were modest differences among women in each tumor
group reporting susceptibility to burn, ability to tan, red
or blonde natural hair color at 20 years of age, and 6 or
more moles on the left upper extremity (Table 2).
RISK OF SKIN CANCER ASSOCIATED
WITH AGE AND UV INDEX OF RESIDENCE
Risk of skin cancer associated with residence in states with
a UV index of 6 and 7 or more compared with residence
in states with a UV index of 5 or less at 3 time points are
presented in
Table 3. There was no association of mela-
noma risk with residence in a state with a UV index of 7
or more at birth or at 15 or 30 years of age. Although the
risk of melanoma was significantly elevated among women
living in states with a UV index of 6 at birth (1.28 [95%
CI, 1.03-1.60]) and 15 years of age (1.32 [95% CI, 1.05-
1.65]), this became nonsignificant at 30 years of age when
adjusting for phenotypic risk factors.
On the other hand, for all 3 age groups, the risks of SCC
and BCC were significantly higher for women living in states
Table 1. Distribution of Skin Cancer-Related Risk Factors and Exposure of Interest
UV Index, % of Participants
a
5 6 7
Birth Age 15 y Age 30 y Birth Age 15 y Age 30 y Birth Age 15 y Age 30 y
No or light tan after2hofsunexposure
as a child
27 27 27 27 27 27 27 26 26
Burn after2hofsunexposure during childhood 31 31 31 33 33 32 31 31 32
Red or blonde natural hair color at 20 y of age 13 13 13 13 13 13 15 15 15
6 Moles on the left upper extremity 2 2 2 2 2 2 1 2 1
a
Described in the “Assessment of Geographic Location” subsection of the “Methods” section.
Table 2. Description of Skin Cancer Data in the NHS
a
1984-2002 Data
Type of Skin Cancer
Melanoma
(n= 420)
SCC
(n= 863)
BCC
(n= 8215)
Person-years of follow-up, millions 1.38 1.38 1.37
Mean age, y
b
59 62 64
UV index of state where born
c
5282530
6615958
7111612
UV index of state of residence at
15yofage
c
5272529
6615859
7121712
UV index of state of residence at
30yofage
c
5252025
6605958
7152117
No or light tan after2hofsun
exposure during childhood
37 36 33
Burn after2hofsun
exposure during childhood
45 44 41
Red or blonde natural hair color at
20yofage
20 22 19
6 Moles on the left upper extremity 4 3 2
Abbreviations: BCC, basal cell carcinoma; NHS, Nurses’ Health Study; SCC,
squamous cell carcinoma.
a
We excluded women with other cancers and those who developed skin
cancer before 1984. Unless otherwise indicated, data are expressed as
percentage of patients.
b
Mean age for the cohort was 56.87 years.
c
Described in the “Assessment of Geographic Location” subsection of the
“Methods” section.
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with UV indices of 6 and 7 or more than for women living
in states with a UV index of 5 or less, and results of the tests
for trend were statistically significant. A trend of increasing
risk of SCC was noted for women living in medium (UV in-
dex, 6) vs high (UV index, 7) UV index locations at all 3
time points (eg, at 30 years of age, for a UV index of 6, 1.47
[95% CI, 1.22-1.76] and, for a UV index of 7, 1.90 [95%
CI, 1.51-2.36]). A similar gradient was noted with increased
risk of BCC when going from medium to high UV index
states (eg, at 30 years of age, for a UV index of 6, 1.19
[95% CI, 1.13-1.26] and, for a UV index of 7, 1.33
[95% CI, 1.23-1.42]). Multivariate analyses adjusting for
natural hair color at 20 years of age, ability to tan, suscep-
tibility to burn, and mole counts on the left upper extrem-
ity did not result in any substantial change compared
with the age-adjusted estimates (Table 3).
Finally, in models restricted to women who had lived
in the same location at all 3 ages to estimate lifetime ex-
posure, the age-adjusted risk of SCC increased from 1.61
(95% CI, 1.31-1.99) to 2.05 (95% CI, 1.54-2.73) in states
with UV indices of 6 and 7 or more, respectively
(
Table 4). The risk of BCC was similar (1.24 [95% CI,
1.17-1.32] and 1.30 [95% CI, 1.18-1.43], respectively)
with the same change in UV index. There was no asso-
ciation of UV index with melanoma.
COMMENT
This prospective study of US women has demon-
strated significant geographic variation in incidence
rates for SCC and BCC (as previously reported) but
not as remarkably for melanoma. The population
under investigation was similarly at risk of all 3 skin
cancers with respect to sun exposure, sun protection
behavior, and occupation. All estimates presented
herein were simultaneously adjusted for phenotypic
risk factors such as natural hair color, susceptibility to
burn, ability to tan, and number of moles on the left
upper extremity. The major difference in our study
was that melanoma risk was not as dependent as SCC
risk was on residence in locations with a higher UV
index (ie, southern states).
46
Table 3. Age-Adjusted and Multivariate Analyses for Melanoma, SCC, and BCC
a
Melanoma SCC BCC
No. of
Cases
RR (95% CI)
No. of
Cases
RR (95% CI)
No. of
Cases
RR (95% CI)
Age Adjusted
b
Multivariate Age Adjusted
b
Multivariate Age Adjusted
b
Multivariate
UV index of state where born
c
5 115 1 [Reference] 1 [Reference] 203 1 [Reference] 1 [Reference] 2268 1 [Reference] 1 [Reference]
6 247 1.28 (1.03-1.60) 1.29 (1.04-1.61) 469 1.39 (1.18-1.64) 1.39 (1.18-1.63) 4476 1.19 (1.13-1.25) 1.19 (1.13-1.25)
7 42 1.07 (0.75-1.52) 1.09 (0.76-1.55) 130 1.82 (1.46-2.27) 1.87 (1.50-2.33) 943 1.22 (1.13-1.32) 1.24 (1.15-1.34)
Total No. of Cases
d
404 802 7687
P value for trend .23 .001 .001
UV index of state of residence
at 15 y of age
c
5 111 1 [Reference] 1 [Reference] 201 1 [Reference] 1 [Reference] 2216 1 [Reference] 1 [Reference]
6 248 1.32 (1.05-1.65) 1.32 (1.06-1.66) 462 1.36 (1.15-1.61) 1.35 (1.15-1.60) 4485 1.20 (1.14-1.27) 1.20 (1.14-1.26)
7 45 1.18 (0.84-1.67) 1.20 (0.85-1.70) 139 1.97 (1.59-2.45) 2.01 (1.61-2.49) 933 1.23 (1.14-1.33) 1.24 (1.15-1.34)
Total No. of Cases
d
404 802 7634
P value for trend .09 .001 .001
UV index of state of residence
at 30 y of age
c
5 99 1 [Reference] 1 [Reference] 154 1 [Reference] 1 [Reference] 1815 1 [Reference] 1 [Reference]
6 234 1.17 (0.92-1.47) 1.17 (0.93-1.48) 456 1.47 (1.22-1.76) 1.46 (1.22-1.76) 4339 1.19 (1.13-1.26) 1.19 (1.12-1.25)
7 61 1.16 (0.84-1.60) 1.17 (0.85-1.61) 159 1.90 (1.51-2.36) 1.90 (1.52-2.37) 1276 1.33 (1.23-1.42) 1.32 (1.23-1.42)
Total No. of Cases
d
394 769 7430
P value for trend .27 .001 .001
Abbreviations: BCC, basal cell carcinoma; CI, confidence interval; RR, relative risk; SCC, squamous cell carcinoma.
a
Multivariate analyses including susceptibility to burn, ability to tan, natural hair color at 20 y of age, and number of moles on left upper extremity.
b
Age was categorized in 5-y increments.
c
Described in the “Assessment of Geographic Location” subsection of the “Methods” section.
d
Total cases are less than in Table 1 because of missing data.
Table 4. Age-Adjusted and Multivariate Analyses Restricted
to Women Who Reported the Same Location for Birth
and Residence at Ages 15 and 30 Years
a
UV Index
a
RR (95% CI)
Age Adjusted Multivariate
Melanoma
5 1 [Reference] 1 [Reference]
6 1.25 (0.97-1.62) 1.26 (0.97-1.63)
7 1.11 (0.72-1.71) 1.12 (0.72-1.72)
SCC
5 1 [Reference] 1 [Reference]
6 1.61 (1.31-1.99) 1.61 (1.31-1.98)
7 2.05 (1.54-2.73) 2.07 (1.55-2.77)
BCC
5 1 [Reference] 1 [Reference]
6 1.24 (1.17-1.32) 1.24 (1.16-1.31)
7 1.30 (1.18-1.43) 1.30 (1.18-1.43)
Abbreviations: BCC, basal cell carcinoma; CI, confidence interval;
RR, relative risk; SCC, squamous cell carcinoma.
a
Described in the “Assessment of Geographic Location” subsection of the
“Methods” section.
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Some previous studies have reported an increased risk
of melanoma,
47,48
whereas other studies have demon-
strated a reduced risk of melanoma with decreasing lati-
tude.
49-51
These effects may be region specific; for ex-
ample, the increased risk with latitude has been well
documented in Europe.
52
This does not imply that mela-
noma occurrence is unrelated to sun or UV expo-
sure
53,54
because we found increased relative risks that
were not statistically significant with residence in loca-
tions with a higher UV index. Darker skin pigmentation
is a protective factor for melanoma.
55,56
Other risk fac-
tors, such as intermittent and intense UV exposure as
would occur in travel to sunny vacations in the middle
of a long winter
57,58
or genetic susceptibility, may play a
more important role in the pathogenesis of melanoma than
that of SCC and BCC, or chronic sun exposure may re-
sult in a tan that may be protective for melanoma spe-
cifically. A north-south gradient has been shown to have
a greater effect on melanoma risk in men compared with
women, and this may also explain our results.
2,59
In our
study, melanoma risk was significantly elevated for women
residing in states with medium UV indices at younger
ages and became nonsignificant for residence in states
with medium UV indices at 30 years of age. A different
pattern of intermittent sun exposure with seasonal change
among women living in regions with medium UV indi-
ces may explain this observation. It is also likely that me-
lanocytes and keratinocytes are differentially sensitive to
UV radiation,
53,60,61
or that the upper bound of the range
of UV exposure in this study is not high enough to affect
melanoma risk. Some of the reported trends in mela-
noma incidence found in previous studies may be ex-
plained by the SEER data for Hawaii, where the UV in-
dex is more than 10. When data from Hawaii were
eliminated, the association between UV exposure and
melanoma became nonsignificant.
35
In the present study,
less than 0.1% of person-time was contributed by women
residing in Hawaii.
A major strength of this study was our ability to
simultaneously evaluate the risks of melanoma, SCC,
and BCC in the same population. The NHS is a cohort
study of a defined population of women with high
rates of follow-up. The crude incidence rates for mela-
noma based on the information presented in Table 2
are higher in the NHS compared with the SEER data-
base. We think this has to do with close follow-up and
case confirmation for melanoma. However, the NHS
population consists only of women, whereas the SEER
database tracks men and women, and the areas of the
country sampled by the SEER database are somewhat
different than the distribution of women in the NHS
across the United States. The relatively homogeneous
nature of our cohort with regard to education, health
awareness, socioeconomic status, and good health care
coverage reduces the variation in sun exposure related
to occupational or behavioral exposure. Hence, our
study evaluated the effect of incidental and recre-
ational exposure as opposed to previous ecologic stud-
ies that may have been influenced by differences in
occupational exposure in states with different climatic
conditions. However, it is also possible that unac-
counted variation in recreational and habitual sun
exposure may have altered risk specifically for mela-
noma in this homogeneous population of US women.
We were also able to control for individual differences
in phenotype such as hair color and susceptibility to
burn, which would confound ecologic analyses if these
phenotypes varied among states of residence. Diagno-
sis of melanoma and SCC was confirmed by medical
record review, eliminating concern for misclassifica-
tion of cases. We restricted this analysis to participants
with incident primary skin cancers and no history of
other cancer to avoid bias resulting from earlier diag-
nosis of skin cancer due to increased awareness and
vigilance among those women. Diagnosis of BCC was
by self-report only and may account for a higher BCC:
SCC ratio in this study. We previously documented
that BCC self-reports are highly valid in this medically
sophisticated population.
45
We did not measure sun exposure directly and used
state of residence as an indirect indicator of sun expo-
sure. The UV index across the United States varies sea-
sonally and, although we chose a particular month (Au-
gust) to divide the country into low, medium, and high
UV index regions, similar UV index trends were noted
in other months of the year and did not affect how the
United States was divided into northern, middle, and
southern states. The reason to use UV indices to divide
the United States into 3 regions was that the UV index
provides more information about ambient UV radiation
than simply latitude of residence. Data were available
on state of residence at 3 time points early in life, but
we have no information about residence for the 15
years between the time points. However, migration
between the UV exposure categories was modest, and
our analysis of risk of the 3 skin cancers among women
who lived at the same location at all 3 time points dem-
onstrates that the overall trends were the same.
CONCLUSIONS
In this study, we found that risk of SCC was associated
with a north-south UV index gradient and increasing
age (as previous studies have reported). Similar trends
were seen for BCC, although they were less pro-
nounced. In contrast to SCC and BCC risks, we found
that melanoma risk was not significantly associated
with the same UV index gradient. These trends
remained unchanged after adjusting for phenotypic risk
factors such as hair color, ability to tan, number of
moles on the left upper extremity, and susceptibility to
burn. In this study, we evaluated a population at similar
risk of all 3 skin cancers as related to sun exposure–
related behavior, yet found differences in risk associated
with residence in different geographic areas. More work
is needed to better understand the mechanisms behind
the observations in this study. Until then we must con-
tinue to investigate the role that UV plays in the patho-
physiological mechanisms of melanoma vs SCC and
BCC. With substantial evidence in the literature of the
protective role played by vitamin D in cancer preven-
tion, those recommending sun protection behaviors
should also promote vitamin D supplementation.
(REPRINTED) ARCH INTERN MED/ VOL 168 (NO. 5), MAR 10, 2008 WWW.ARCHINTERNMED.COM
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Accepted for Publication: October 5, 2007.
Correspondence: Abrar A. Qureshi, MD, MPH, Depart-
ment of Dermatology, Channing Laboratory (Depart-
ment of Medicine), Brigham and Women’s Hospital, 45
Francis St, Boston, MA 02115 (aqureshi@partners.org).
Author Contributions: Study concept and design: Qureshi,
Laden, and Hunter. Acquisition of data: Qureshi, Laden,
and Hunter. Analysis and interpretation of data: Qureshi,
Laden, Colditz, and Hunter. Drafting of the manuscript:
Qureshi, Laden, and Colditz. Critical revision of the manu-
script for important intellectual content: Qureshi, Laden,
and Hunter. Statistical analysis: Qureshi, Laden, and
Hunter. Obtained funding: Qureshi. Administrative, tech-
nical, and material support: Qureshi, Colditz, and Hunter.
Financial Disclosure: None reported.
Funding/Support: This study was supported in part by
a Career Development Award in Health Care Policy from
the Dermatology Foundation (Dr Qureshi) and grant
K07CA10897 from the National Cancer Institute (Dr
Qureshi).
Additional Contributions: Robert Stern, MD, provided
helpful comments on this manuscript.
REFERENCES
1. Almahroos M, Kurban AK. Ultraviolet carcinogenesis in nonmelanoma skin can-
cer, I: incidence rates in relation to geographic locations and in migrant populations.
Skinmed. 2004;3(1):29-36.
2. Bulliard JL. Site-specific risk of cutaneous malignant melanoma and pattern of
sun exposure in New Zealand. Int J Cancer. 2000;85(5):627-632.
3. Bataille V, Boniol M, De Vries E, et al. A multicentre epidemiological study on
sunbed use and cutaneous melanoma in Europe. Eur J Cancer. 2005;41(14):
2141-2149.
4. Grant WB. An ecologic study of cancer mortality rates in Spain with respect to
indices of solar UVB irradiance and smoking. Int J Cancer. 2007;120(5):1123-
1128.
5. Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of co-
lon cancer [originally published in Int J Epidemiol. 1980;9(3):227-231]? Int J
Epidemiol. 2006;35(2):217-220.
6. Garland CF, Garland FC, Gorham ED, et al. The role of vitamin D in cancer prevention.
Am J Public Health. 2006;96(2):252-261.
7. Grant WB, Garland CF. The association of solar ultraviolet B (UVB) with reduc-
ing risk of cancer: multifactorial ecologic analysis of geographic variation in age-
adjusted cancer mortality rates. Anticancer Res. 2006;26(4)(suppl A):2687-
2699.
8. Freedman DM, Dosemeci M, McGlynn K. Sunlight and mortality from breast, ovar-
ian, colon, prostate, and non-melanoma skin cancer: a composite death certifi-
cate based case-control study. Occup Environ Med. 2002;59(4):257-262.
9. Tuohimaa P, Tenkanen L, Syva¨la¨ H, et al. Interaction of factors related to the meta-
bolic syndrome and vitamin D on risk of prostate cancer. Cancer Epidemiol Bio-
markers Prev. 2007;16(2):302-307.
10. Giovannucci E, Liu Y, Willett WC. Cancer incidence and mortality and vitamin D
in black and white male health professionals. Cancer Epidemiol Biomarkers Prev.
2006;15(12):2467-2472.
11. Norval M, Cullen AP, de Gruijl FR, et al. The effects on human health from strato-
spheric ozone depletion and its interactions with climate change. Photochem Pho-
tobiol Sci. 2007;6(3):232-251.
12. Abarca JF, Casiccia CC. Skin cancer and ultraviolet-B radiation under the Ant-
arctic ozone hole: southern Chile, 1987-2000. Photodermatol Photoimmunol
Photomed. 2002;18(6):294-302.
13. Kinney JP, Long CS. The Ultraviolet Index: a useful tool. Dermatol Online J. 2000;
6(1):2.
14. Schmalwieser AW, Schauberger G, Janouch M, et al. Global forecast model to
predict the daily dose of the solar erythemally effective UV radiation. Photo-
chem Photobiol. 2005;81(1):154-162.
15. Coldiron BM. The UV Index: a weather report for skin. Clin Dermatol. 1998;16(4):
441-446.
16. Blunden A, Lower T, Slevin T. Knowledge, awareness, and use of the UV index
amongst the West Australian public. J Health Commun. 2004;9(3):207-221.
17. Brooks KR, Brooks DR, Hufford D, Samenow J, Geller AC. Are television sta-
tions and weather pages still reporting the UV index? a national media follow-up
study. Arch Dermatol. 2005;141(4):526.
18. Suzuki T, Ueda M, Ogata K, Horikoshi T, Munakata N, Ichihashi M. Doses of so-
lar ultraviolet radiation correlate with skin cancer rates in Japan. Kobe J Med Sci.
1996;42(6):375-388.
19. Correˆa MP, Dubuisson P, Plana-Fattori A. An overview of the ultraviolet index
and the skin cancer cases in Brazil. Photochem Photobiol. 2003;78(1):49-54.
20. Magnus K. The Nordic profile of skin cancer incidence: a comparative epidemiologi-
cal study of the three main types of skin cancer. Int J Cancer. 1991;47(1):12-19.
21. Ramos J, Villa J, Ruiz A, Armstrong R, Matta J. UV dose determines key char-
acteristics of nonmelanoma skin cancer. Cancer Epidemiol Biomarkers Prev. 2004;
13(12):2006-2011.
22. Urbach F. Incidence of nonmelanoma skin cancer. Dermatol Clin. 1991;9(4):751-755.
23. Vitaliano PP, Urbach F. The relative importance of risk factors in nonmelanoma
carcinoma. Arch Dermatol. 1980;116(4):454-456.
24. English DR, Armstrong BK, Kricker A, Winter MG, Heenan PJ, Randell PL. Case-
control study of sun exposure and squamous cell carcinoma of the skin. Int J
Cancer. 1998;77(3):347-353.
25. Armstrong BK, Kricker A, English DR. Sun exposure and skin cancer. Australas
J Dermatol. 1997;38(suppl 1):S1-S6.
26. Hemminki K, Zhang H, Czene K. Incidence trends and familial risks in invasive
and in situ cutaneous melanoma by sun-exposed body sites. Int J Cancer. 2003;
104(6):764-771.
27. Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis of risk factors for cutane-
ous melanoma, II: sun exposure. Eur J Cancer. 2005;41(1):45-60.
28. Kennedy C, Bajdik CD, Willemze R, et al. The influence of painful sunburns and
lifetime sun exposure on the risk of actinic keratoses, seborrheic warts, mela-
nocytic nevi, atypical nevi, and skin cancer. J Invest Dermatol. 2003;120(6):
1087-1093.
29. Ford D, Bliss JM, Swerdlow AJ, et al; International Melanoma Analysis Group
(IMAGE). Risk of cutaneous melanoma associated with a family history of the
disease. Int J Cancer. 1995;62(4):377-381.
30. Urbach F. Ultraviolet radiation and skin cancer of humans. J Photochem Photo-
biol B. 1997;40(1):3-7.
31. Jemal A, Devesa SS, Fears TR, Hartge P. Cancer surveillance series: changing
patterns of cutaneous malignant melanoma mortality rates among whites in the
United States. J Natl Cancer Inst. 2000;92(10):811-818.
32. Lee JA, Scotto J. Melanoma: linked temporal and latitude changes in the United
States. Cancer Causes Control. 1993;4(5):413-418.
33. Green A, McCredie M, Giles G, Jackman L. Occurrence of melanomas on the up-
per and lower limbs in eastern Australia. Melanoma Res. 1996;6(5):387-394.
34. Crombie IK. Variation of melanoma incidence with latitude in North America and
Europe. Br J Cancer. 1979;40(5):774-781.
35. Eide MJ, Weinstock MA. Association of UV index, latitude, and melanoma inci-
dence in nonwhite populations: US Surveillance, Epidemiology, and End Re-
sults (SEER) Program, 1992 to 2001. Arch Dermatol. 2005;141(4):477-481.
36. Scotto J, Fears TR. The association of solar ultraviolet and skin melanoma incidence
among Caucasians in the United States. Cancer Invest. 1987;5(4):275-283.
37. Hu S, Ma F, Collado-Mesa F, Kirsner RS. UV radiation, latitude, and melanoma
in US Hispanics and blacks. Arch Dermatol. 2004;140(7):819-824.
38. Fears TR, Bird CC, Guerry D IV, et al. Average midrange ultraviolet radiation flux
and time outdoors predict melanoma risk. Cancer Res. 2002;62(14):3992-
3996.
39. Huber M, Blumthaler M, Schreder J, Bais A, Topaloglou C. Effect of ambient tem-
perature on Robertson-Berger–type erythemal dosimeters. Appl Opt. 2002;
41(21):4273-4277.
40. Tatalovich Z, Blumthaler M, Schreder J, Bais A, Topaloglou C. The objective as-
sessment of lifetime cumulative ultraviolet exposure for determining melanoma
risk. J Photochem Photobiol B. 2006;85(3):198-204.
41. Garland FC, White MR, Garland CF, Shaw E, Gorham ED. Occupational sunlight
exposure and melanoma in the US Navy. Arch Environ Health. 1990;45(5):
261-267.
42. Bo¨ni R, Schuster C, Nehrhoff B, Burg G. Epidemiology of skin cancer. Neuro En-
docrinol Lett. 2002;23(suppl 2):48-51.
43. Elder DE. Skin cancer: melanoma and other specific nonmelanoma skin cancers.
Cancer. 1995;75(1)(suppl):245-256.
44. Colditz GA, Martin P, Stampfer MJ, et al. Validation of questionnaire information
on risk factors and disease outcomes in a prospective cohort study of women.
Am J Epidemiol. 1986;123(5):894-900.
45. Hunter DJ, Colditz GA, Stampfer MJ, Rosner B, Willett WC, Speizer FE. Diet and
risk of basal cell carcinoma of the skin in a prospective cohort of women. Ann
Epidemiol. 1992;2(3):231-239.
46. Armstrong BK, Kricker A. The epidemiology of UV induced skin cancer. J Pho-
tochem Photobiol B. 2001;63(1-3):8-18.
(REPRINTED) ARCH INTERN MED/ VOL 168 (NO. 5), MAR 10, 2008 WWW.ARCHINTERNMED.COM
506
©2008 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ on 02/25/2013
Page 6
47. Oliveria SA, Saraiya M, Geller AC, Heneghan MK, Jorgensen C. Sun exposure
and risk of melanoma. Arch Dis Child. 2006;91(2):131-138.
48. Armstrong BK. Epidemiology of malignant melanoma: intermittent or total ac-
cumulated exposure to the sun? J Dermatol Surg Oncol. 1988;14(8):
835-849.
49. Lee JA. The relationship between malignant melanoma of skin and exposure to
sunlight. Photochem Photobiol. 1989;50(4):493-496.
50. Moan J, Dahlback A, Setlow RB. Epidemiological support for an hypothesis for
melanoma induction indicating a role for UVA radiation. Photochem Photobiol.
1999;70(2):243-247.
51. Lee JA. Declining effect of latitude on melanoma mortality rates in the United
States: a preliminary study. Am J Epidemiol. 1997;146(5):413-417.
52. Boniol M, Dore´ JF, Autier P, Smans M, Boyle P. Descriptive epidemiology of skin
cancer incidence and mortality. In: Ringborg U, Brandberg Y, Breitbart EW, Grein-
ert R, eds. Skin Cancer Prevention. New York, NY: Informa Healthcare; 2007:
203-223.
53. Christophers AJ. Melanoma is not caused by sunlight. Mutat Res. 1998;422(1):
113-117.
54. Sinha T, Benedict R. Relationship between latitude and melanoma incidence: in-
ternational evidence. Cancer Lett. 1996;99(2):225-231.
55. Agar N, Young AR. Melanogenesis: a photoprotective response to DNA damage?
Mutat Res. 2005;571(1-2):121-132.
56. Yamaguchi Y, Takahashi K, Zmudzka BZ, et al. Human skin responses to UV ra-
diation: pigment in the upper epidermis protects against DNA damage in the lower
epidermis and facilitates apoptosis. FASEB J. 2006;20(9):1486-1488.
57. Bentham G, Aase A. Incidence of malignant melanoma of the skin in Norway,
1955-1989: associations with solar ultraviolet radiation, income and holidays
abroad. Int J Epidemiol. 1996;25(6):1132-1138.
58. Agredano YZ, Chan JL, Kimball RC, Kimball AB. Accessibility to air travel corre-
lates strongly with increasing melanoma incidence. Melanoma Res. 2006;16
(1):77-81.
59. Bulliard JL, Cox B, Elwood JM. Latitude gradients in melanoma incidence and
mortality in the non-Maori population of New Zealand. Cancer Causes Control.
1994;5(3):234-240.
60. Wang LE, Xiong P, Strom SS, et al. In vitro sensitivity to ultraviolet B light and
skin cancer risk: a case-control analysis. J Natl Cancer Inst. 2005;97(24):1822-
1831.
61. Hussein MR. Ultraviolet radiation and skin cancer: molecular mechanisms. J Cu-
tan Pathol. 2005;32(3):191-205.
(REPRINTED) ARCH INTERN MED/ VOL 168 (NO. 5), MAR 10, 2008 WWW.ARCHINTERNMED.COM
507
©2008 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ on 02/25/2013
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  • Source
    • "Another study of 5700 melanoma cases worldwide found a 1.5-fold increased risk when living at latitudes closer than 20° from the equator [31]. Importantly, though latitude risk for melanoma has been historically strong, recent studies suggest decreased correlation [32], or even an opposite trend. A 2012 study of Northern Europeans, for example, showed an increase in melanoma incidence with increase in latitude beyond 50° north of the equator [33], perhaps due to the dramatic rise in artificial indoor tanning. "
    [Show abstract] [Hide abstract] ABSTRACT: Being the largest and most visible organ of the body and heavily influenced by environmental factors, skin is ideal to study the long-term effects of aging. Throughout our lifetime, we accumulate damage generated by UV radiation. UV causes inflammation, immune changes, physical changes, impaired wound healing and DNA damage that promotes cellular senescence and carcinogenesis. Melanoma is the deadliest form of skin cancer and among the malignancies of highest increasing incidence over the last several decades. Melanoma incidence is directly related to age, with highest rates in individuals over the age of 55 years, making it a clear age-related disease. In this review, we will focus on UV-induced carcinogenesis and photo aging along with natural protective mechanisms that reduce amount of "realized" solar radiation dose and UV-induced injury. We will focus on the theoretical use of forskolin, a plant-derived pharmacologically active compound to protect the skin against UV injury and prevent aging symptoms by up-regulating melanin production. We will discuss its use as a topically-applied root-derived formulation of the Plectranthus barbatus (Coleus forskolii) plant that grows naturally in Asia and that has long been used in various Aryuvedic teas and therapeutic preparations.
    Full-text · Article · May 2014 · Molecules
  • Source
    • "These dose–response relations remained the same after adjusting for other skin cancer risk factors. Previous findings from this cohort suggest that sun exposure intensity in early life may increase the risk of skin cancer in adulthood (Qureshi et al, 2008). Results from the present study provide further evidence that the quantity of sun exposure received over long durations in adulthood as indicated by cumulative UV flux may also increase the risk of skin cancer, particularly for SCC. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Solar ultraviolet (UV) exposure estimated based on residential history has been used as a sun exposure indicator in previous case–control and descriptive studies. However, the associations of cumulative UV exposure based on residential history with different skin cancers, including melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC), have not been evaluated simultaneously in prospective studies. Methods: We conducted a cohort study among 108 578 women in the Nurses' Health Study (1976–2006) to evaluate the relative risks of skin cancers with cumulative UV flux based on residential history in adulthood. Results: Risk of SCC and BCC was significantly lower for women in lower quintiles vs the highest quintile of cumulative UV flux (both P for trend <0.0001). The association between cumulative UV flux and risk of melanoma did not reach statistical significance. However, risk of melanoma appeared to be lower among women in lower quintiles vs the highest quintile of cumulative UV flux in lag analyses with 2–10 years between exposure and outcome. The multivariable-adjusted hazard ratios per 200 × 10−4 Robertson–Berger units increase in cumulative UV flux were 0.979 (95% confidence interval (CI): 0.933, 1.028) for melanoma, 1.072 (95% CI: 1.041, 1.103) for SCC, and 1.043 (95% CI: 1.034, 1.052) for BCC. Conclusions: Associations with cumulative UV exposure in adulthood among women differed for melanoma, SCC, and BCC, suggesting a potential variable role of UV radiation in adulthood in the carcinogenesis of the three major skin cancers.
    Full-text · Article · Mar 2014 · British Journal of Cancer
  • Source
    • "Since equatorial locations tend to be warm and conducive to recreational or occupational outdoor activities, people living such locales typically wear less clothing and have more contact with ambient sunlight and usually receive much higher ambient UV doses than persons inhabiting temperate climates. Not surprisingly, skin cancer risk generally mirrors this geographic pattern, particularly among fair-skinned sun-sensitive persons444546. "
    [Show abstract] [Hide abstract] ABSTRACT: UV radiation (UV) is classified as a "complete carcinogen" because it is both a mutagen and a non-specific damaging agent and has properties of both a tumor initiator and a tumor promoter. In environmental abundance, UV is the most important modifiable risk factor for skin cancer and many other environmentally-influenced skin disorders. However, UV also benefits human health by mediating natural synthesis of vitamin D and endorphins in the skin, therefore UV has complex and mixed effects on human health. Nonetheless, excessive exposure to UV carries profound health risks, including atrophy, pigmentary changes, wrinkling and malignancy. UV is epidemiologically and molecularly linked to the three most common types of skin cancer, basal cell carcinoma, squamous cell carcinoma and malignant melanoma, which together affect more than a million Americans annually. Genetic factors also influence risk of UV-mediated skin disease. Polymorphisms of the melanocortin 1 receptor (MC1R) gene, in particular, correlate with fairness of skin, UV sensitivity, and enhanced cancer risk. We are interested in developing UV-protective approaches based on a detailed understanding of molecular events that occur after UV exposure, focusing particularly on epidermal melanization and the role of the MC1R in genome maintenance.
    Full-text · Article · Jun 2013 · International Journal of Molecular Sciences
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